Angiogenesis, the development of new vasculature from preexisting blood vessels, plays a critical role in many physiological processes and pathological events. An increased understanding of how angiogenesis is regulated in tissues would contribute to a variety of biological and medical areas. The extracellular matrix (ECM) and matricellular proteins found in the ECM function as important regulators of angiogenesis by their interaction with endothelial cells and the angiogenic factors that control blood vessel development. SPARC (secreted protein, acidic and rich in cysteine), a matricellular protein, has recently been shown to interact with and regulate the activity of vascular endothelial growth factor (VEGF), a primary stimulant of angiogenesis in both normal and pathological situations. An understanding of the proteins in the ECM that interact with VEGF and their ability to regulate VEGF activity would contribute to our understanding of VEGF-induced angiogenesis and its role in tissue homeostasis and pathology. In this application I will characterize further the interaction of SPARC and VEGF. The ability of SPARC to block VEGF from activating VEGFR1 an VEGFR2 will be determined and the ability of SPARC to regulate VEGF activities including: migration of endothelial cells, chemotaxis of macrophages, and vascular permeability will be examined.